c-Abl phosphorylates Hdm2 at tyrosine 276 in response to DNA damage and regulates interaction with ARF.

The p53 tumour-suppressor protein is tightly regulated through its association with the Hdm2 E3 ligase. Activation of p53 by DNA strand breaks is orchestrated by the ataxia-telangiectasia mutated (ATM) protein kinase and involves interruption of Hdm2-mediated p53 degradation. As part of this mechanism ATM itself, and the ATM-activated protein tyrosine ...
kinase, c-Abl, inhibit Hdm2 function through phosphorylation of serine 395 and tyrosine 394 (Y394), respectively. In the present study, we have identified a novel target of c-Abl in the Hdm2 protein, tyrosine 276 (Y276). We show that c-Abl phosphorylates this residue in vitro and confirm that Y394 is a target of c-Abl. We also show that Y276 is phosphorylated in a c-Abl-dependent manner in cultured cells and provide evidence that Y276 is phosphorylated in response to DNA damage coincident with the activation of c-Abl. Finally, we show that Y276 phosphorylation stimulates interaction with ARF, leading to increased levels of nucleolar Hdm2 and decreased turnover of p53. These data establish Y276 as a physiological target of c-Abl that contributes functionally to the induction of p53.
Mesh Terms:
Animals, Ataxia Telangiectasia Mutated Proteins, COS Cells, Cell Cycle Proteins, Cells, Cultured, Cercopithecus aethiops, Cyclin-Dependent Kinase Inhibitor p16, DNA Damage, DNA-Binding Proteins, Humans, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-abl, Proto-Oncogene Proteins c-mdm2, Transfection, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Oncogene
Date: Oct. 26, 2006
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